What are the key principles of preventing yeast/molds - Candida?

Most infections due to Candidaspp. arise from an individual's own flora (i.e., they are endogenous). Since Candidais a normal commensal flora, it requires a breach in the host's anti-Candida barrier in order to invade and cause infection.

The most common breaches in the anti-Candida barrier that increase the risk for Candida infections include:

Use of intravascular devices (primarily central venous catheters), which may allow vascular access to Candida colonizing the skin, or may become infected by Candida that enter the bloodstream from other locations (e.g., the gut).

Use of cytotoxic drugs, which can result in neutropenia (neutrophils and innate immunity being a key component of host defense) and mucositis (which also disrupts the mucosal barrier to Candida invasion).

Preventing Candida spp. infections involves avoiding or minimizing the impact of these breaches in the anti-Candida barrier. This means (1) practicing good antimicrobial stewardship, (2) reducing the use of intravascular devices, in particular central venous catheters, and (3) meticulous implementation of the central line-associated bloodstream infection (CLABSI) prevention bundles.

Excellent hand hygiene is one component of the CLABSI prevention bundle, and remains one of the cornerstones of preventing Candida infections. Even though Candida infections are largely endogenous, the hands of healthcare workers can serve as one reservoir for nosocomial transmission of Candida species.

While the above prevention approaches are the primary means for preventing Candida infection, some breaches in the anti-Candida barrier are inevitable, and some patients remain at an unacceptably high risk for invasive Candida spp. infections.

These patients are candidates for antifungal prophylaxis. The most common antifungal prophylaxis regimen used for prevention of Candida infection is fluconazole at a dose of 400mg (6mg/kg) daily.

Candidates for antifungal prophylaxis include:

Patients with chemotherapy-induced neutropenia.

High-risk solid organ transplant recipients during the post-operative period (e.g., liver transplant with two or more additional risk factors such as renal failure, retransplantation, fungal colonization, intraoperative transfusion of greater than 40 units of blood products, or prolonged intraoperative time).

High-risk intensive care unit (ICU) patients (e.g., central venous catheter, antimicrobial exposure, receipt of total parenteral nutrition, Candida colonization at one or more body sites, GI surgery) in units with a high incidence of invasive candidiasis.

What are the key conclusions for available clinical trials and meta-analyses that inform control of yeast/molds - Candida?

There are no clinical trials or meta-analyses that examine the role of hand hygiene and antimicrobial stewardship specifically to reduce the incidence of Candida infections.

The recommendation for hand hygiene interventions is based upon studies that show a reduction in overall nosocomial infection rates after improvement in hand hygiene performance, and the evidence that healthcare worker hands can serve as vehicles for Candida transmission in healthcare settings.

The recommendation for antimicrobial stewardship is based upon studies showing the very strong relationship between antimicrobial exposure and risk for invasive candidiasis (a risk which increases with each additional antimicrobial agent).

The largest multicenter trial of CLABSI prevention bundles describes a 66% reduction in CLABSI among the 103 ICUs reporting data. This reduction is similar in magnitude to reductions reported in single center studies.

Candida spp. are the third most common cause of CLABSI in United States (U.S.) ICUs, so it is assumed that successful CLABSI prevention will also prevent candidemia.

However, existing studies do not identify Candida spp. infections as a specific outcome measure, though some single center studies report encouraging results (e.g., the study by Coopersmith, et al., reported nine episodes of candidemia in the 18 month period prior to a CLABSI prevention program, and no episodes of candidemia in the 18 months after the intervention).

There are many clinical trials examining the role of antifungal prophylaxis in preventing Candida spp. infections, which can be summarized for three major high risk groups: non-neutropenic ICU patients, neutropenic cancer patients (including hematopoietic stem cell transplant (HSCT)), and solid organ transplant patients.

Non-neutropenic intensive care unit patients

Trials examining the use of prophylaxis in non-neutropenic ICU patients are well summarized in published meta-analyses. These analyses reveal that the use of prophylaxis (generally fluconazole 400mg/day) effectively reduces the incidence of invasive candidiasis.

However, these studies all took place in ICUs that had high baseline rates of invasive candidiasis (often greater than 10%, compared with the usual ICU rate of 1-2%).

In addition, neither the single center studies nor the meta-analyses support a mortality benefit from this practice. Therefore, the routine use of antifungal prophylaxis in non-neutropenic ICU patients is not recommended.

It should be considered, however, for patients at high risk for invasive candidiasis in ICUs that have high baseline rates of Candida spp. infections (despite efforts to improve hand hygiene, antimicrobial stewardship, and CLABSI prevention). See the current controversies section for more details.

Neutropenic cancer patients

A meta-analysis summarizing data on antifungal prophylaxis in neutropenic cancer patients also revealed a reduction in the incidence of Candida spp. infections. For selected subgroups (prolonged neutropenia and HSCT), a mortality benefit was also demonstrated.

The 38 trials included in this meta-analysis included use of a variety of azoles or of amphotericin B. For some populations of cancer patients (e.g., prolonged neutropenia, HSCT, or graft-versus-host disease), prophylaxis with agents that have anti-mold activity (specifically, posaconazole 200mg po three times a day and micafungin 50gm IV/day) have been demonstrated to reduce not only Candida spp. infections but all invasive fungal infections (e.g., Aspergillus) as well.

Several studies have demonstrated a reduction in Candida spp. infections among high-risk solid organ transplant recipients.

The key conclusions from these trials, as summarized in the Infectious Diseases Society of America (IDSA) guideline, are that fluconazole (400mg/day) or liposomal amphotericin B (1-2mg/kg/day) is recommended for 7-14 days postoperatively for:

What are the consequences of ignoring key concepts related to control of yeast/molds - Candida?

Healthcare-associated bloodstream infections due to Candida have a very high attributable mortality (between 15-49%), and increase the cost of care by up to $40,000. Ignoring key aspects of prevention and control of nosocomial candidiasis carries a very high price indeed, in lives lost and in increased cost of care. (Figure 1) (Figure 2)

Figure 1

Figure 2

Summary of current controversies.

Current controversies around the prevention of nosocomial candidiasis include: Is antifungal prophyaxis indicated for ICU patients at increased risk for candidemia? When is early empiric therapy for invasive candidiasis indicated?

ICU patients are at high risk for nosocomial candidiasis, and antifungal prophylaxis has been demonstrated to reduce this risk. However, such prophylaxis has not yet been shown to reduce mortality, and widespread use of antifungal agents in the ICU population may lead to the emergence of antifungal resistance, and also carries with it increased risk for drug interactions and side effects.

Work is now underway to determine if prediction rules can help define a high risk ICU population so that prophylaxis can be limited only to that subset, thereby limiting the untoward effects of widespread antifungal use.

The diagnosis of Candida infections is often delayed, due to slow or absent growth in culture and delays in antifungal therapy have been demonstrated to result in increased mortality.

Therefore, early empiric therapy (treatment for suspected invasive candidiasis prior to confirmation of the diagnosis) is indicated in selected patients. However, it is still not clear exactly when such therapy is indicated.

What is the role of and impact of yeast/molds - Candida or infections and the need for control relative to infections at other sites or other specific pathogens?

Candida species are the most common cause of invasive fungal infection in healthcare settings. A recent multicenter survey conducted in the U.S. from 2004-2008 found that Candida spp. accounted for 75% of invasive fungal infections in hospitalized patients.

From 1995 to 2002, the frequency of nosocomial candidemia in U.S. hospitals rose significantly from 8% to 12% of all reported bloodstream infections (BSI); and Candidainfections are now the third leading cause of CLABSI in U.S. ICUs.

Not only is invasive candidiasis common, but it also carries with it a very high crude and attributable mortality. In a recent survey of nosocomial infections in U.S. hospitals, Candida bloodstream infections were associated with the highest crude mortality among other common causes of nosocomial bloodstream infection.

Recently, researchers estimated the burden of early-onset candidemia in ICU patients at 176 acute care hospitals, and found that candidemia was associated with significantly greater mortality, longer hospital stays, and higher hospital costs than were bloodstream infections due to bacterial pathogens.

Given how common and how deadly healthcare-associated invasive Candida infections are, their prevention should be a priority for infection prevention programs.

Overview of important clinical trials, meta-analyses, case control studies, case series, and individual case reports related to infection control and yeast/molds - Candida.

See Table I, Table II, and Table III.

Table I.

Impact of early-onset candidemia relative to that of bacterial pathogens in the intensive care unit

Type of bloodstream infection

Parameter

Candida species

Gram-positive

Gram-negative

Mortality (%)

28

20

10

Length of stay (days)

14

11

8

Cost ($ U.S.)

30,219

18,526

12,305

Table II.

Impact of delays in antifungal therapy on hospital mortality

% Mortality

Reference

Patient stratum

N patients

% Mortality (hour delay)

% Mortality with no delay

Morrell, 2005

All

157

33.1 (>12)

11.1

PMID:16127033

APACHE II <= 15

90

23.5 (>12)

0.0

APACHE II > 15

67

46.0 (>12)

25.0

Garey, 2006

All

230

23.7 (24)

15.4

PMID:16758414

36.4 (48)

41.4 (>=72)

Table III.

Meta-analyses of azole prophylaxis to prevent candidiasis in the intensive care unit

Study

N

Odds ratio or relative risk for IFI

Odds ratio or relative risk for mortality

Shorr, et al. PMID16148461

626

0.4 (95% CI, 0.3-0.7)

0.9 (0.6-1.3)

Playford, et al. PMID16459344

1606

0.5 (0.3-0.7)

0.8 (0.6-1.0)

Vardakas, et al.PMID16484923

847

0.2 (0.1-0.3)

0.7 (0.5-1.1)

Controversies in detail.

As summarized previously, current controversies around the prevention of nosocomial candidiasis include: Is antifungal prophylaxis indicated for ICU patients at increased risk for candidemia? When is early empiric therapy for invasive candidiasis indicated?

Antifungal prophylaxis

Many studies have examined the effectiveness of antifungal prophylaxis in high-risk ICU patients. These studies demonstrate that the use of azole prophylaxis (e.g. fluconazole 400mg per day) can effectively decrease the incidence of invasive candidiasis in ICU patients.

However, because these studies do not demonstrate an impact on overall mortality, and because the widespread use of antifungal agents may lead to the emergence of antifungal resistance, some feel that this approach to prevention is not indicated.

One reasonable approach is to select only the highest risk ICU patients for such prophylaxis. Several prediction rules have been proposed, but the rule most extensively validated in a multicenter study is as follows: receipt of systemic antibiotics OR presence of a central venous catheter AND at least TWO of the following: total parenteral nutrition, dialysis, major surgery, pancreatitis, or use of steroids or other immunosuppressive agents.

Ostrosky-Zeichner and colleagues recently published a variation of this rule requiring mechanical ventilation AND central venous catheter AND broad-spectrum antibiotics AND an additional risk factor. This new rule applied to 18% of ICU patients in their validation study, and this group had an invasive candidiasis rate of 10% (a rate high enough that benefit from prophylaxis is anticipated).

Multicenter studies are now ongoing to determine if application of these prediction rules to guide prophylaxis can effectively reduce the incidence of nosocomial candidiasis and reduce mortality.

Lack of specific clinical findings and delays in diagnosis result in failure to recognize and treat invasive candidiasis in a timely manner. Furthermore, delays in receipt of appropriate therapy have been shown to result in increased mortality from candidemia.

Early empiric therapy

Similar to the question of who may benefit from prophylaxis for candidemia, it is still unclear exactly which patients should be given early empiric therapy for invasive candidiasis.

Such therapy should be considered for critically ill patients who have fever without known cause and risk factors for invasive candidiasis, especially those who have received broad-spectrum antibiotics and have Candida colonization at one or more body sites.

However, in the largest randomized controlled trial of early empiric therapy, in which adult ICU patients with fever despite broad-spectrum antibiotics received fluconazole 800mg/day or placebo, there was no difference in the composite primary outcome (resolution of fever, absence of invasive fungal infection, lack of toxicity, and absence of need for a non-study antifungal agent).

Fewer fungal infections than anticipated occurred in the control group of this study, and Candida colonization at other body sites was not included among the criteria for enrolment.

Further study is needed to determine the optimal approach to early empiric therapy. Ultimately, the solution to timely therapy may be found in better and faster diagnostic tests that do not require growth in culture.

The role of more rapid, non-culture based tests for invasive candidiasis remains to be determined. The best candidate test at this time is the beta-D-glucan test, which on a recent evaluation had a sensitivity of 87% and specificity of 73% for invasive candidiasis in a surgical trauma ICU.

In the future we hope for better rapid diagnostics to help shorten the time to effective therapy while focusing the use of systemic antifungal agents only to those who will obtain a benefit.

What national and international guidelines exist related to yeast/molds - Candida?

The major national guidelines are published and updated by the Infectious Diseases Society of America, and were most recently updated in 2009.

The CDC, the Infectious Disease Society of America, and the American Society of Blood and Marrow Transplantation have also published a joint guideline on the prevention of opportunistic infections in hematopoietic stem cell transplant patients that includes guidance on prevention of fungal infections such as invasive candidiasis.

Similar guidelines have been published for solid organ transplant patients.

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